The first part of the project is concerned with the changes which take place in pancreatic B-cells when they are in a diabetic (hyperglycemic) milieu. It is hypothesized that chronic hyperglycemia produces marked changes in B-cell function and structure. Rat models will be used and these employ chemical and surgical reduction of B-cell mass, and glucose infusions. The focus will be upon insulin secretion and biosynthesis, and B-cell mass and growth capacity. These studies should provide new insights into the pathogenesis of diabetes mellitus. The second part of the project is concerned with the interrelationships which take place between the different cellular elements of islets. Studies will be carried out in human pancreatic tissue to determine the relationship of islet vasculature to the B-cell core and the non-B-cell mantle of islets. In addition, assessment will be made of polarity of A, B and D cells. These studies should further our understanding of the functional compartmentalization which is present in islets.